This laboratory has been working towards characterizing the possible receptor mechanisms for the therapeutic and side effects of the estrogenic component of the oral contraceptives. A binding system for estradiol has recently been found in the mammalian liver. It has been postulated that this estrogen binding in liver may be involved in production of the side effects by increasing synthesis of selective plasma prote1ns including clotting factors (involved in thromboembolism), renin substrate (involved in hypertension or lipoproteins (potentially involved in accelerating atherosclerosis). This binding system differs from that in the sites of therapeutic action of the estrogen the hypothalamus and pituitary for inhibition of ovulation and the uterus for regularity of menses. The following studies are proposed: Study the high affinity binding to find estrogen derivatives which in vitro and in vivo interact less with the liver binding system than with the hypothalamus, pituitary and uterus, purify the binding proteins with affinity chromatography, attempt to correlate the presence of the liver binding system to estrogen inducibility of selective plasma proteins synthesis, study tissue culture lines of hepatomas hepatomas for estrogen binding and induction of selective plasma protein synthesis, elucidate control of the development of the liver binding protein, observe if estrogens induce early synthesis of one protein fraction in target organs other than the uterus, and eventually evaluate potentially better estrogens in higher mammals for inhibition of ovulation without increasing plasma levels of plasma proteins including renin substrate and clotting factors potentially involved in producing the side effects.